Antagonists of gonadotropin releasing hormone

ABSTRACT

There are disclosed compounds of formula (I) ##STR1## and pharmaceutically acceptable salts thereof which are useful as antagonists of GnRH and as such may be useful for the treatment of a variety of sex-hormone related and other conditions in both men and women.

This application claims the domestic priority of Ser. No. 60/048,743,Jun. 5, 1997 and Ser. No. 60/048,635 Jun. 5, 1997.

BACKGROUND OF THE INVENTION

The gonadotropin-releasing hormone (GnRH), also referred to asluteinizing hormone-releasing hormone (LHRH), is a decapeptide thatplays a key role in human reproduction. The hormone is released from thehypothalamus and acts on the pituitary gland to stimulate thebiosynthesis and secretion of luteinizing hormone (LH) andfollicle-stimulating hormone (FSH). LH released from the pituitary glandis primarily responsible for the regulation of gonadal steroidproduction in both sexes, whereas FSH regulates spermatogenesis in malesand follicular development in females. GnRH agonists and antagonistshave proven effective in the treatment of certain conditions whichrequire inhibition of LH/FSH release. In particular, GnRH-basedtherapies have proven effective in the treatment of endometriosis,uterine fibroids, polycystic ovarian disease, precocious puberty andseveral gonadal steroid-dependent neoplasia, most notably cancers of theprostate, breast and ovary. GnRH agonists and antagonists have also beenutilized in various assisted fertilization techniques and have beeninvestigated as a potential contraceptive in both men and women. Theyhave also shown possible utility in the treatment of pituitarygonadotrophe adenomas, sleep disorders such as sleep apnea, irritablebowel syndrome, premenstrual syndrome, benign prostatic hyperplasia,hirsutism, as an adjunct to growth hormone therapy in growth hormonedeficient children, and in murine models of lupus.

Current GnRH antagonists are GnRH-like decapeptides which are generallyadministered intravenously or subcutaneously presumably because ofnegligible oral activity. These have amino acid substitutions usually atpositions one, two, three, six and ten.

Non-peptide GnRH antagonists offer the possible advantage of oraladminstration. Non-peptide GnRH antagonists have been described inEuropean Application 0 219 292 and in De, B. et al., J. Med. Chem., 32,2036-2038 (1989), in WO 95/28405, WO 95/29900 and EP 0679642 all toTakeda Chemical Industries, Ltd.

Substituted indoles known in the art include those described in thefollowing patents and patent applications. U.S. Pat. No. 5,030,640discloses alpha-heterocyclic ethanol aminoalkyl indoles which are potentβ-agonists. U.S. Pat. No. 4,544,663 discloses indolamine derivativeswhich are allegedly useful as male anti-fertility agents. WO 90/05721discloses alpha-amino-indole-3-acetic acids useful as anti-diabetic,anti-obesity and anti-atherosclerotic agents. French patent 2,181,559discloses indole derivatives with sedative, neuroleptic, analgesic,hypotensive, antiserotonin and adrenolytic activity. Belgian patent879381 discloses 3-aminoalkyl-1H-indole-5-thioamide and carboxamidederivatives as cardiovascular agents used to treat hypertension,Raynaud's disease and migraine. WO 97/21435, WO 97/21703, WO 97/21707and WO 97/21704 disclose non-peptidyl, indole derivatives as GnRHantagonists.

SUMMARY OF THE INVENTION

The present invention relates to compounds which are non-peptideantagonists of GnRH which can be used to treat a variety of sex-hormonerelated conditions in men and women, to methods for their preparation,and to methods and pharmaceutical compositions containing said compoundsfor use in mammals.

Because of their activity as antagonists of the hormone GnRH, thecompounds of the present invention are useful to treat a variety ofsex-hormone related conditions in both men and women. These conditionsinclude endometriosis, uterine fibroids, polycystic ovarian disease,hirsutism, precocious puberty, gonadal steroid-dependent neoplasias suchas cancers of the prostate, breast and ovary, gonadotrophe pituitaryadenomas, sleep apnea, irritable bowel syndrome, premenstrual syndromeand benign prostatic hypertophy. They are also useful as an adjunct totreatment of growth hormone deficiency and short stature, and for thetreatment of systemic lupus erythematosis. Further, the compounds of theinvention may be useful in in vitro fertilization and as contraceptives.The compounds may also be useful in combination with androgens,estrogens, progesterones, antiestrogens and antiprogestogens for thetreatment of endometriosis, fibroids and in contraception. They may alsobe useful in combination with testosterone or other androgens orantiprogestogens in men as a contraceptive. The compounds may also beused in combination with an angiotensin-converting enzyme inhibitor suchas Enalapril or Captopril, an angiotensin II-receptor antagonist such asLosartan or a renin inhibitor for the treatment of uterine fibroids.Additionally, the compounds of the invention may also be used incombination with bisphosphonates (bisphosphonic acids) and other agents,such as growth hormone secretagogues, e.g. MK-0677, for the treatmentand prevention of disturbances of calcium, phosphate and bonemetabolism, in particular, for the prevention of bone loss duringtherapy with the GnRH antagonist, and in combination with estrogens,progesterones, antiestrogens, antiprogestins and/or androgens for theprevention or treatment of bone loss or hypogonadal symptoms such as hotflashes during therapy with the GnRH antagonist.

Additionally, a compound of the present invention may be co-administeredwith a 5a-reductase 2 inhibitor, such as finasteride or epristeride; a5a-reductase 1 inhibitor such as 4,7b-dimethyl-4-aza-5a-cholestan-3-one,3-oxo-4-aza-4,7b-dimethyl-16b-(4-chlorophenoxy)-5a-androstane, and3-oxo-4-aza-4,7b-dimethyl-16b-(phenoxy)-5a-androstane as disclosed in WO93/23420 and WO 95/11254; dual inhibitors of 5a-reductase 1 and5a-reductase 2 such as3-oxo-4-aza-17b-(2,5-trifluoromethylphenyl-carbamoyl)-5a-androstane asdisclosed in WO 95/07927; antiandrogens such as flutamide, casodex andcyproterone acetate, and alpha-1 blockers such as prazosin, terazosin,doxazosin, tamsulosin, and alfuzosin.

Further, a compound of the present invention may be used in combinationwith growth hormone, growth hormone releasing hormone or growth hormonesecretagogues, to delay puberty in growth hormone deficient children,which will allow them to continue to gain height before fusion of theepiphyses and cessation of growth at puberty.

Further, a compound of the present invention may be used in combinationor co-administered with a compound having luteinizing hormone releasingactivity such as a peptide or natural hormone or analog thereof. Suchpeptide compounds include leuprorelin, gonadorelin, buserelin,triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterlin andrecirelin.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of the general formula##STR2## wherein A is R₂₂ -[heteroaryl]-R₂₂ - or R₂₂ -[substitutedheteroaryl]-R₂₂ -;

B is optionally absent, --OR₂₂ --, --C(═O)R₂₂ --, --S(O)_(n) R₂₂ --,--NR₁₈ R₂₂ --, --OC(═O)R₂₂ --, --C(═O)OR₂₂, --OS(O)_(n) R₂₂ -- or--S(O)_(n) OR₂₂ --;

R₀ is hydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, wherein thesubstituents are as defined below; aryl, substituted aryl, aralkyl orsubstituted aralkyl, wherein the substituents are as defined for R₃, R₄and R₅ ;

R₁ is ##STR3## the nitrogen atoms contained in the R₁ heteroaromaticrings may exist either as drawn or, when chemically allowed, in theiroxidized (NR→O) state;

R₂ is heteroaryl, substituted heteroaryl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl; or

R₂ is A--B--R₁ ; or

R₂ and A can optionally be taken together to form a ring of 5-7 atoms;

R₃, R₄ and R₅ are independently hydrogen, C₁ -C₆ alkyl, substituted C₁-C₆ alkyl, C₂ -C₆ alkenyl, substituted C₂ -C₆ alkenyl, CN, nitro, C₁ -C₃perfluoroalkyl, C₁ -C₃ perfluoroalkoxy, aryl, substituted aryl, aralkyl,substituted aralkyl, R₁₁ O(CH₂)_(p) --, (CH₂)_(p) S(O)_(n) R₁₇ orhalogen; wherein R₁₇ is hydrogen, C₁ -C₆ alkyl, C₁ -C₃ perfluoroalkyl,aryl or substituted aryl; or

R₃ and R₄ taken together form a carbocyclic ring of 3-7 carbon atoms ora heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

R₆ is hydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, aryl,substituted aryl, C₁ -C₃ perfluoroalkyl, CN, NO₂, halogen, R₁₆O(CH₂)_(p) --;

R₇ is hydrogen, C₁ -C₆ alkyl, or substituted C₁ -C₆ alkyl, unless X ishydrogen or halogen, then R₇ is absent;

R₈ is hydrogen, C(O)OR₉, C(O)NR₁₁ R₁₂, NR₁₁ R₁₂, C(O)R₁₁, NR₁₂ C(O)R₁₁,NR₁₂ C(O)NR₁₁ R₁₂, NR₁₂ S(O)₂ R₁₁, NR₁₂ S(O)₂ NR₁₁ R₁₂, OC(O)R₁₁,OC(O)NR₁₁ R₁₂, OR₁₁, SO_(n) R₁₁, S(O)_(n) NR₁₁ R₁₂, a heterocyclic ringor bicyclic heterocyclic ring with from 1 to 4 heteroatoms selected fromN, O or S which can be optionally substituted by R₃, R₄ and R₅, C₁ -C₆alkyl or substituted C₁ -C₆ alkyl, unless X is hydrogen or halogen, thenR₈ is absent; or

R₇ and R₈ taken together form a heterocyclic ring containing one or moreheteroatoms selected from N, O or S which can be optionally substitutedby R₃, R₄ and R₅ ; or

R₇ and R₈ taken together form a carbocyclic ring of 3-7 atoms or##STR4## when m≠0; R₉ and R_(9a) are independently hydrogen, C₁ -C₆alkyl, substituted C₁ -C₆ alkyl; aryl or substituted aryl, aralkyl orsubstituted aralkyl when m≠0; or

R₉ and R_(9a) taken together form a carbocyclic ring of 3-7 atoms or##STR5## when m≠0; R₁₀ and R_(10a) are independently hydrogen, C₁ -C₆alkyl, substituted C₁ -C₆ alkyl, aryl, substituted aryl, aralkyl orsubstituted aralkyl; or

R₁₀ and R_(10a) taken together form a carbocyclic ring of 3-7 atoms or##STR6## R₉ and R₁₀ when taken together form a carbocyclic ring of 3-7carbon atoms or a heterocyclic ring containing one or more heteroatomswhen m≠0; or R₉ and R₂ taken together form a heterocyclic ringcontaining 3-7 carbon atoms and one or more heteroatoms when m≠0; or

R₁₀ and R₂ taken together form a heterocyclic ring containing 3-7 carbonatoms and one or more heteroatoms;

R₁₁ and R₁₂ are independently a bond, hydrogen, C₁ -C₆ alkyl,substituted C₁ -C₆ alkyl, aryl, substituted aryl, aralkyl, substitutedaralkyl, a carbocyclic ring of 3-7 atoms, a substituted carbocyclic ringcontaining 3-7 atoms, a heterocyclic ring or bicyclic heterocyclic ringwith from 1 to 4 heteroatoms selected from N, O or S which can beoptionally substituted by R₃, R₄ and R₅, C₁ -C₆ -alkyl substituted by aheterocyclic ring or bicyclic heterocyclic ring with from 1 to 4heteroatoms selected from N, O or S which can be optionally substitutedby R₃, R₄ and R_(5;)

R₁₁ and R₁₂ when taken together can form an optionally substituted ringof 3-9 atoms;

R₁₃ is hydrogen, OH, NR₇ R₉, NR₁₆ SO₂ (C₁ -C₆ alkyl), NR₁₆ SO₂(substituted C₁ -C₆ alkyl), NR₁₆ SO₂ (aryl), NR₁₆ SO₂ (substitutedaryl), NR₁₆ SO₂ (C₁ -C₃ perfluoroalkyl); SO₂ NR₁₆ (C₁ -C₆ alkyl), SO₂NR₁₁ (substituted C₁ -C₆ alkyl), SO₂ NR₁₁ (aryl), SO₂ NR₁₆ (substitutedaryl), SO₂ NR₁₆ (C₁ -C₃ perfluoroalkyl); SO₂ NR₁₆ (C(O)C₁ -C₆ alkyl);SO₂ NR₁₆ (C(O)-- substituted C₁ -C₆ alkyl); SO₂ NR₁₆ (C(O)-aryl); SO₂NR₁₆ (C(O)-substituted aryl); S(O)_(n) (C₁ -C₆ alkyl); S(O)_(n)(substituted C₁ -C₆ alkyl), S(O)_(n) (aryl), S(O)_(n) (substitutedaryl), C₁ -C₃ perfluoroalkyl, C₁ -C₃ perfluoroalkoxy, C₁ -C₆ alkoxy,substituted C₁ -C₆ alkoxy, COOH, halogen, NO₂ or CN;

R₁₄ and R₁₅ are independently hydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆alkyl, C₂ -C₆ alkenyl, substituted C₂ -C₆ alkenyl, CN, nitro, C₁ -C₃perfluoroalkyl, C₁ -C₃ perfluoroalkoxy, aryl, substituted aryl, aralkyl,substituted aralkyl, R₁₆ O(CH₂)_(p) --, R₁₆ C(O)O(CH₂)_(p) --, R₁₆OC(O)(CH₂)_(p) --, --(CH₂)_(p) S(O)_(n) R₁₇, --(CH₂)_(p) C(O) N(R₁₆)₂ orhalogen; wherein R₁₇ is hydrogen, C₁ -C₆ alkyl, C₁ -C₃ perfluoroalkyl,aryl or substituted aryl;

R₁₆ is hydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, aryl,substituted aryl, aralkyl, substituted aralkyl, a carbocyclic ring of3-7 atoms or a substituted carbocyclic ring containing 3-7 atoms;

R₁₈ is hydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, C(O)OR₁₆,C(O)N(R₁₆)₂, C(O)R₁₆, S(O)_(n) R₁₆ ;

R₁₉ is either the definition of R₁₃ or R₁₄ ;

R₂₂ is C₀ -C₄ alkyl, substituted C₁ -C₄ alkyl;

X is N, O, S(O)_(n), C(O), (CR₁₁ R₁₂)_(p), a single bond to R₈, C₂ -C₆alkenyl, substituted C₂ -C₆ alkenyl,C₂ -C₆ alkynyl, or substituted C₂-C₆ alkynyl; when X is O, S(O)n, C(O), or CR₁₁ R₁₂ only R₈ is possible;

Z is o, S or NR₁₁ ;

m is 0, 1, 2 or 3;

n is 0, 1 or 2;

p is 0, 1, 2, 3 or 4; and the alkyl, cycloalkyl, alkenyl and alkynylsubstituents are selected from C₁ -C₆ alkyl, C₃ -C₇ cycloalkyl, aryl,substituted aryl, aralkyl, substituted aralkyl, hydroxy, oxo, cyano, C₁-C₆ alkoxy, fluoro, C(O)OR₁₁, aryl C₁ -C₃ alkoxy, substituted aryl C₁-C₃ alkoxy, and the aryl substituents are as defined for R₃, R₄ and R₅ ;or a pharmaceutically acceptable addition salt and/or hydrate thereof,or where applicable, a geometric or optical isomer or racemic mixturethereof.

In a preferred embodiment, there are disclosed compounds of formula Iwherein

A is R₂₂ -[thiophene]-R₂₂ -;

R₀ is hydrogen;

R₁ is ##STR7## the nitrogen atoms contained in the R₁ heteroaromaticrings may exist either as drawn or, when chemically allowed, in theiroxidized (N→O) state;

R₃, R₄ and R₅ are independently hydrogen, C₁ -C₆ alkyl, substituted C₁-C₆ alkyl or halogen;

R₈ is C(O)NR₁₁ R₁₂, or

R₁₁ and R₁₂ are independently a bond, hydrogen, C₁ -C₆ alkyl,substituted C₁ -C₆ alkyl, aryl, substituted aryl, aralkyl, substitutedaralkyl, a carbocyclic ring of 3-7 atoms, a substituted carbocyclic ringcontaining 3-7 atoms, a heterocyclic ring or bicyclic heterocyclic ringwith from 1 to 4 heteroatoms selected from N, O or S which can beoptionally substituted by R₃, R₄ and R₅, C₁ -C₆ -alkyl substituted by aheterocyclic ring or bicyclic heterocyclic ring with from 1 to 4heteroatoms selected from N, O or S which can be optionally substitutedby R₃, R₄ and R_(5;)

R₁₁ and R₁₂ when taken together can form an optionally substituted ringof 3-9 atoms;

X is (CR₁₁ R₁₂)_(p) ;

or a pharmaceutically acceptable addition salt and/or hydrate thereof,or where applicable, a geometric or optical isomer or racemic mixturethereof.

Preferred substituents when R₁₁ and R₁₂ are taken together include7-aza-bicyclo[2.2.1]heptane and 2-aza-bicyclo[2.2.2] octane.

Unless otherwise stated or indicated, the following definitions shallapply throughout the specification and claims.

When any variable (e.g., aryl, heterocycle, R₁, etc.) occurs more thanone time in any constituent or in formula I, its definition on eachoccurrence is independent of its definition at every other occurrence.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

The term "alkyl" is intended to include both branched- andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, e.g., methyl (Me), ethyl (Et), propyl,butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decyl, undecyl, dodecyl,and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu),sec-butyl (s-Bu), tert-butyl (t-Bu), isopentane, isohexane, etc.

The term "aryl" includes phenyl and naphthyl. Preferably, aryl isphenyl.

The term "heteroaryl" is intended to include the compounds shown below:##STR8## where Z is O, S, or NR₁₁, as well as the following compounds:##STR9##

The term "halogen" or "halo" is intended to include fluorine, chlorine,bromine and iodine.

The term "heterocycle" or "heterocyclic ring" is defined by allnon-aromatic, heterocyclic rings of 3-7 atoms containing 1-3 heteroatomsselected from N, O and S, such as oxirane, oxetane, tetrahydrofuran,tetrahydropyran, pyrrolidine, piperidine, tetrahydropyridine,tetrahydropyrimidine, tetrahydrothiophene, tetrahydrothiopyran,morpholine, hydantoin, valerolactam, pyrrolidinone, and the like.

As used herein, the term "composition" is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

In addition, it is well known to those skilled in the art that many ofthe foregoing heterocyclic groups can exist in more than one tautomericform. It is intended that all such tautomers be included within theambit of this invention.

The optical isomeric forms, that is mixtures of enantiomers, e.g.,racemates, or diastereomers as well as individual enantiomers ordiastereomers of the instant compound are included. These individualenantiomers are commonly designated according to the optical rotationthey effect by the symbols (+) and (-), (L) and (D), (1) and (d) orcombinations thereof. These isomers may also be designated according totheir absolute spatial configuration by (S) and (R), which stands forsinister and rectus, respectively.

The individual optical isomers may be prepared using conventionalresolution procedures, e.g., treatment with an appropriate opticallyactive acid, separating the diastereomers and then recovering thedesired isomer. In addition, the individual optical isomers may beprepared by asymmetric synthesis.

Additionally, a given chemical formula or name shall encompasspharmaceutically acceptable addition salts thereof and solvates thereof,such as hydrates.

The compounds of the present invention, while effective themselves, maybe formulated and administered in the form of their pharmaceuticallyacceptable addition salts for purposes of stability, convenience ofcrystallization, increased solubility and other desirable properties.

The compounds of the present invention may be administered in the formof pharmaceutically acceptable salts. The term "pharmaceuticallyacceptable salt" is intended to include all acceptable salts. Examplesof acid salts are hydrochloric, nitric, sulfuric, phosphoric, formic,acetic, trifluoroacetic, propionic, maleic, succinic, malonic, methanesulfonic and the like which can be used as a dosage form for modifyingthe solubility or hydrolysis characteristics or can be used in sustainedrelease or prodrug formulations. Depending on the particularfunctionality of the compound of the present invention, pharmaceuticallyacceptable salts of the compounds of this invention include those formedfrom cations such as sodium, potassium, aluminum, calcium, lithium,magnesium, zinc, and from bases such as ammonia, ethylenediamine,N-methyl-glutamine, lysine, arginine, ornithine, choline,N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine,N-benzylphenethylamine, diethylamine, piperazine,tris(hydroxymethyl)aminomethane, and tetramethyl-ammonium hydroxide.These salts may be prepared by standard procedures, e.g. by reacting afree acid with a suitable organic or inorganic base, or alternatively byreacting a free base with a suitable organic or inorganic acid.

Also, in the case of an acid (--COOH) or alcohol group being present,pharmaceutically acceptable esters can be employed, e.g. methyl, ethyl,butyl, acetate, maleate, pivaloyloxymethyl, and the like, and thoseesters known in the art for modifying solubility or hydrolysischaracteristics for use as sustained release or prodrug formulations.

The compounds of the present invention may have chiral centers otherthan those centers whose stereochemistry is depicted in formula I, andtherefore may occur as racemates, racemic mixtures and as individualenantiomers or diastereomers, with all such isomeric forms beingincluded in the present invention as well as mixtures thereof.Furthermore, some of the crystalline forms for compounds of the presentinvention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe instant invention may form solvates with water or common organicsolvents. Such solvates are encompassed within the scope of thisinvention.

The compounds of the invention are prepared by the following reactionschemes. All substituents are as defined above unless indicatedotherwise. ##STR10##

Reaction Scheme A

As shown in reaction Scheme A, treatment of tryptamine (1) withN-carboxyphthalimide in an inert organic solvent such as tetrahydrofuranat a temperature of 20-65° C., preferably 65° C., for a period of 12-48hours gives the corresponding N-phthalimidotryptamine derivative (2).The N-phthalimidotryptamine (2) could be further modified by treatmentwith a brominating agent such as pyridinium hydrobromide perbromide,pyrrolidone hydrotribromide, or the like in an inert organic solventsuch as tetrahydrofuran, methylene chloride, chloroform, or mixturesthereof at 0-25° C. for a period of 30 minutes to 4 hours to provide the2-bromotryptamine (3). Bromide (3) may be reacted with an arylboronicacid (prepared essentially as described in: Gronowitz, S.; Hornfeldt, A.-B.; Yang, Y. -H. Chem. Scr. 1986,26, 311-314.) with palladium (0)catalysis, a weak base such as aqueous sodium carbonate or the like, anda chloride source such as lithium chloride in an inert solvent liketoluene, benzene, ethanol, propanol or mixtures thereof at a temperatureof 25°-100° C., preferably 80° C., for a period of 1-6 hours to give the2-aryltryptamine derivative (4). Finally, the phthalimido group may beremoved by treatment of (4) with aqueous hydrazine in an inert solventsuch as methanol or ethanol at a temperature of 0°-256C for a period of4-24 hours to give tryptamine (5). ##STR11##

Reaction Scheme B

As shown in reaction Scheme B, the 2-aryltryptamine may be condensedwith a carboxylic acid of type (6) using the coupling reagent1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC),1,3-dicyclohexylcarbodiimide (DCC) or the like with or without1-hydroxybenzotriazole (HOBt) and a tertiary amine base such asN-methylmorpholine (NMM), triethylamine or the like in an inert organicsolvent such as methylene chloride, chloroform, dimethylformamide, ormixtures thereof at or near room temperature for a period of 3-24 hoursto provide the corresponding amide derivative (7). Alternatively,2-aryltryptamine (5) can be treated with an active ester or acidchloride of type (8) in an inert organic solvent such as methylenechloride, chloroform, tetrahydrofuran, diethyl ether, or the like and atertiary amine base such as triethylamine, diisopropylethylamine,pyridine or the like at a temperature of 0°-25° C. for 30 minutes to 4hours to give (7). ##STR12##

Reaction Scheme C

As shown in reaction Scheme C, the amide carbonyl of (7) can be reducedby treatment with borane, lithium aluminum hydride, or equivalenthydride sources in an inert organic solvent such as tetrahydrofuran,diethyl ether, 1,4-dioxane or the like at 25°-100° C., preferably 65°C., for a period of 1-8 hours to give the corresponding amine compound(9). ##STR13##

Reaction Scheme D

As shown in reaction Scheme D, the 2-aryltryptamine (23 or 5) can bemodified by treatment with an aldehyde or ketone of type (10a or 10b) inthe presence of a weak acid such as trifluoroacetic acid (TFA), aceticacid or the like, with or without a dessicant such as 3 Å molecularsieves or magnesium sulfate, and a hydride source such as sodiumborohydride or sodium cyanoborohydride, in an inert organic solvent suchas methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane,chloroform, or mixtures thereof at a temperature of 0°-25° C. for aperiod of 1-12 hours to give the corresponding secondary or tertiaryamine derivative (11). ##STR14##

Reaction Scheme E

As shown in reaction Scheme E, treatment of an arylhydrazine orarylhydrazine hydrochloride (12) with an arylcyclopropylketone of type(13) in a polar organic solvent such as methanol, ethanol, n-propanol,isopropanol, n-butanol, t-butanol, preferably n-butanol, at atemperature of 70°-120° C. for a period of 8-24 hours gives2-aryltryptamine (5). Alternatively, when an arylhydrazine orarylhydrazine hydrochloride (12) is treated with an arylbutyl ketone oftype (14) containing a leaving group (chloride, bromide, iodide,O-methansulfonate, O-trifluoromethansulfonate, or the like) at the4-position in a polar solvent such as methanol, ethanol, n-propanol,isopropanol, n-butanol, t-butanol, or mixtures thereof at roomtemperature for a period of 30 minutes to 2 hours followed by heating toa temperature of 65°-100° C. for 4-24 hours, 2-aryltryptamine (5) isproduced. ##STR15##

Reaction Scheme F

As shown in reaction Scheme F, iodoanilines of type (15) may be reactedwith aryl acetylenes, an appropriate palladium (0) catalyst such astetrakis(triphenylphosphine)palladium, a copper (I) halide such ascuprous bromide in an inert organic solvent such as triethylamine at atemperature of 50°-88° C. for a period of 30 minutes to 5 hours toprovide the diarylacetylene (16). Acetylene (16) may be further modifiedby treatment with a palladium (II) catalyst such as palladium (II)chloride or palladium (II) acetate in an inert organic solvent such asacetonitrile at a temperature of 50°-82° C. for a period of 30 minutesto 6 hours to give 2-arylindole (17). ##STR16##

Reaction Scheme G

As shown in reaction Scheme G, treatment of 2-arylindole (17) withoxalyl chloride neat or in an inert organic solvent such as methylenechloride, chloroform, dichloroethane, tetrahydrofuran or the like at atemperature of 25°-65° C. for a period of 3-24 hours gives theacylchloride adduct (18). The crude product (18) may be reacted with anamine of type (19) in an inert organic solvent such as diethylether,tetrahydrofuran, methylene chloride, chloroform or the like and an aminebase such as triethylamine, diisopropylethylamine or pyridine at atemperature of 0° C.-25° C. for a period of 30 minutes to 4 hours toprovide the amide derivative (20). Amide (20) may be further modified bytreatment with a reducing agent such as borane or lithium aluminumhydride in an inert organic solvent such as tetrahydrofuran at elevatedtemperatures, preferably reflux, for a period of 1-5 hours to givecompound (21). ##STR17##

Reaction Scheme H

As shown in reaction Scheme H, N-benzyl derivatives of type (22a) orN-benzyloxycarbonyl derivatives of type (22b) may be reduced to providethe secondary amine analogs (7) by treatment with hydrogen (1 atm) andan appropriate catalyst such as palladium on carbon, palladium hydroxideon carbon, or the like in an inert organic solvent such astetrahydrofuran, ethyl acetate, methanol, ethanol, or mixtures thereofto which has been added a weak acid such as 30% aqueous acetic acid fora period of 10 minutes to 3 hours or until the aryl group has beenremoved to give the secondary amine. ##STR18##

Reaction Scheme I

As shown in reaction Scheme I, treatment of a nitroindole of type (24)with hydrogen (1 atm) and an appropriate catalyst such as Raney® Nickelin an inert organic solvent such as ethanol, methanol, or the like atroom temperature for a period of 2-12 hours gives the correspondingaminoindole derivative (25). ##STR19##

Reaction Scheme J

As shown in reaction Scheme J, amino- or hydroxyindole (25) may bemodified by acylation under a variety of conditions. For example,treatment of (25) with an acid chloride, acid anhydride or active esterand an amine base such as triethylamine, diisopropylethylamine,pyridine, or the like in an inert organic solvent such as methylenechloride, chloroform, tetrahydrofuran, or mixtures thereof at 0° C. toroom temperature for a period of 1 to 12 hours gives the correspondingamide or ester derivatives (26). Alternatively (25) may be coupled witha carboxylic acid by one of the many dehydrating agents commonlyemployed. For instance, treatment of aminoindole (25) with anappropriate carboxylic acid and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC),1,3-dicyclohexylcarbodiimide (DCC) or the like with or without1-hydroxybenzotriazole (HOBt) and a tertiary amine base such asN-methylmorpholine (NMM), triethylamine or the like in an inert organicsolvent such as methylene chloride, chloroform, dimethylformamide, ormixtures thereof at or near room temperature for a period of 3-24 hoursprovides the corresponding amide or ester derivative (26). ##STR20##

Reaction Scheme K

As shown in reaction Scheme K, urea or carbamate derivatives of (25) canbe prepared by treatment with a carbamoyl chloride of type (27a), oralternatively with an isocyanate reagent of type (27b), and an aminebase such as pyridine, triethylamine, diisopropylethylamine,N-methylmorpholine or the like in an inert organic solvent such asmethylene chloride, chloroform, dimethylformamide, tetrahydrofuran ormixtures thereof at a temperature of 0°-65° C. for a period of 1-72hours to give (28). Compound (25) can also be modified by treatment witha bis(electrophilic) reagent such as phosgene, triphosgene,1,1'-carbonyldiimidazole, N,N'-disuccinimidyl carbonate, or the likewith or without the addition of an amine base such as pyridine,triethylamine, diisopropylethylamine, N-methylmorpholine in an inertsolvent such as methylene chloride, chloroform, or the like at atemperature of -20°-0°C. for a period of 20 minutes to 2 hours. Afterthis time, the reaction mixture is treated with an appropriate mono- ordisubstituted amine at -20° to 250° C. for a period of 1-5 hours to givethe urea or carbamate analog (28). ##STR21##

Reaction Scheme L

As shown in reaction Scheme L, amine (25) can be modified by treatmentwith an appropriate sulfonyl chloride of type (29) or sulfamyl chlorideof type (30) with an amine base such as pyridine, triethylamine,diisopropylethylamine, N-methylmorpholine in an inert solvent such asmethylene chloride, chloroform, dichloroethane or the like at atemperature of -20°-25° C. for a period of 20 minutes to 2 hours to givethe corresponding N-sulfonamide (31) or N-sulfamylamide (32)derivatives, respectively. ##STR22##

Reaction Scheme M

As shown in reaction Scheme M, the 2-aryltryptamine (33) can be modifiedby treatment with an epoxide such as (34) in an inert organic solventsuch as methanol, ethanol, isopropanol, butanol, tert-butanol, ormixtures thereof at a temperature of 65°-110° C. for a period of 8-20hours to give the corresponding amino-alcohol derivative (35). ##STR23##

Reaction Scheme N

As shown in reaction Scheme N, amide derivatives of an acid-containingindole derivative such as (36) can be prepared by treatment with anappropriate amine (R₁₂ R₁₁ NH) and a suitable coupling agent such asbenzotriazol-1-yloxy-tris(pyrrolidino) phosphonium hexafluorophosphate(PyBOP), benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate (BOP), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (DCC) or the like withor without 1-hydroxybenzotriazole (HOBt) and a tertiary amine base suchas N-methylmorpholine (NMM), triethylamine or the like in an inertorganic solvent such as methylene chloride, chloroform, tetrahydrofuran,dimethylformamide, or mixtures thereof at or near room temperature for aperiod of 3 hours to 7 days provides the corresponding amide derivative(37). ##STR24##

Reaction Scheme O

As shown in reaction Scheme O, the tryptamine 5 can be modified byreaction with an arylsufonyl chloride such as 2-nitrobenzenesulfonylchloride, 4-nitrobenzenesulfonyl chloride or 2,4-dinitrobenzenesulfonylchloride and a hindered amine base such as 2,4,6-collidine, 2,6-lutidineor the like in an inert organic solvent such as methylene chloride toprovide the corresponding sulfonamide 38. Sulfonamides such as 38 can befurther modified by reaction with an alcohol of type 39 in the presenceof triphenylphosphine and an activating agent such as diethylazodicarboxylate (DEAD), diisopropyl azodicaboxylate or the like in aninert organic solvent such as benzene, toluene, tetrahydrofuran ormixtures thereof to give the dialkylsulfonamide adduct. Removal of thesulfonyl group is accomplished by treatment with a nucleophilic aminesuch as n-propylamine or the like in an inert organic solvent such asmethylene chloride to give secondary amines of type 23.

The compounds of the present invention are useful in the treatment ofvarious sex-hormone related conditions in men and women. This utility ismanifested in their ability to act as antagonists of the neuropeptidehormone GnRH as demonstrated by activity in the following in vitroassays.

Human GnRH receptor binding assay

Crude membranes prepared from CHO cells expressing human GnRH receptorswere the sources for GnRH receptor. [¹²⁵ I]Buserelin (a peptidyl GnRHanalog) was used as the radiolabelled ligand. The binding activity wasdetermined as an IC₅₀ which is the antagonist concentration required toinhibit the specific binding of [¹²⁵ I]buserelin to GnRH receptors by50%.

Rat pituitary GnRH receptor binding assay:

Crude plasma membranes prepared from rat pituitary tissues wereincubated in a Tris.HCl buffer (50 mM, PH. 7.5) containing bovine serumalbumin (0.1%), [I-125]D-t-Bu-Ser6-Pro9-ethyl amide-GnRH, and thedesired concentration of a test compound. The assay mixtures wereincubated at 4° C. for 90-120 minutes followed by rapid filtration andrepeated washings through a glass fiber filter. The radioactivity ofmembrane bound radioligands was determined in a gamma-counter. From thisdata, the IC₅₀ of the radioligand binding to GnRH receptors in thepresence of test compound was estimated.

Inhibition of LH release assay:

Active compounds from the GnRH receptor binding assay were furtherevaluated with an in vitro LH release assay to confirm their antagonistactivity (blocking GnRH-induced LH release).

1. Sample Preparation

The compounds to be assayed were dissolved and diluted in DMSO. Thefinal concentration of DMSO in the incubation medium was 0.5%.

2. Assay

The Wistar male rats (150-200 grams) were obtained from Charles RiverLaboratories (Wilmington, Mass.). Rats were maintained at a constanttemperature (25° C.) on a 12-hr light, 12-hr dark cycle. Rat chow andwater were available ad libitum. The animals were sacrificed bydecapitation and pituitary glands were aseptically removed and placed inHank's Balanced Salt Solution (HBBSS) in a 50-mL polypropylenecentrifuge tube. The collection tube was centrifuged for 5 min at 250×g, and HBSS was removed by aspiration. Pituitary glands were transferredto a disposable petri plate and minced with a scalpel. The minced tissuewas then transferred to a 50-mL disposable centrifuge tube by suspendingthe tissue fragments in three successive 10-mL aliquots of HBSScontaining 0.2% collagenase and 0.2% hyaluronidase. The cell dispersionwas carried out in a water bath at 37° C. with gentle stirring for 30min. At the end of the incubation, the cells were aspirated 20 to 30times with a pipet and the undigested pituitary fragments were allowedto settle for 3 to 5 min. The suspended cells were removed byaspiration, and then subjected to a 1200× g centrifugation for 5 min.The cells were then resuspended in Culture medium. The undigestedpituitary fragments were treated with 30 mL aliquots of the digestionenzymes as above for a total of 3 digestions with thecollagenase/hyaluronidase mixture. The resulting cell suspensions werepooled, counted and diluted to a concentration of 3×10⁵ cells/ml, and1.0 ml of this suspension was placed in each well of a 24-well tray(Costar, Cambridge, Mass.). Cells were maintained in a humidified 5% CO₂-95% air atmosphere at 37° C. for 3 to 4 days. The culture mediumconsisted of DMEM containing 0.37% NaHCO₃, 10% horse serum, 2.5% fetalbovine serum, 1% non-essential amino acids, 1% glutamine, and 0.1%gentamycin. On the day of an experiment, cells were washed three times11/2 hrs prior to and two more times immediately before the start of theexperiment with DMEM containing 0.37% NaHCO₃, 10% horse serum, 2.5%fetal bovine serum, 1% non-essential amino acids(100×), 1%glutamine(100×), 1% Penicillin/Streptomycin(10,000 Units of Penicillinand 10,000 micrograms of Streptomycin per ml), and 25 mM HEPES, pH 7.4.LH release was initiated by adding 1 ml of fresh medium containing testcompounds in the presence of 2 nM GnRH to each well in duplicate.Incubation was carried out at 37° C. for 3 hr. After incubation, mediumwas removed and centrifuged at 2,000× g for 15 min to remove anycellular material. The supernatant fluid was removed and assayed for LHcontent with a double antibody RIA procedure using materials obtainedfrom Dr. A. F. Parlow (Harbor-UCLA Medical Center, Torrance, Calif.).

The compounds of formula I are useful in a number of areas affected byGnRH. They may be useful in sex-hormone related conditions, sex-hormonedependent cancers, benign prostatic hypertrophy or myoma of the uterus.Sex-hormone dependent cancers which may benefit from the administrationof the compounds of this invention include prostatic cancer, uterinecancer, breast cancer and pituitary gonadotrophe adenomas. Othersex-hormone dependent conditions which may benefit from theadministration of the compounds of this invention include endometriosis,polycystic ovarian disease, uterine fibroids and precocious puberty. Thecompounds may also be used in combination with an angiotensin-convertingenzyme inhibitor such as Enalapril or Captopril, an angiotensinII-receptor antagonist such as Losartan or a renin inhibitor for thetreatment of uterine fibroids.

The compounds of the invention may also be useful for controllingpregnancy, as a contraceptive in both men and women, for in vitrofertilization, in the treatment of premenstrual syndrome, in thetreatment of lupus erythematosis, in the treatment of hirsutism, in thetreatment of irritable bowel syndrome and for the treatment of sleepdisorders such as sleep apnea.

A further use of the compounds of this invention is as an adjunct togrowth hormone therapy in growth hormone deficient children. Thecompounds may be administered with growth hormone or a compound whichincreases the endogenous production or release of growth hormone.Certain compounds have been developed which stimulate the release ofendogenous growth hormone. Peptides which are known to stimulate therelease of endogenous growth hormone include growth hormone releasinghormone, the growth hormone releasing peptides GHRP-6 and GHRP-1(described in U.S. Pat. No. 4,411,890, PCT Patent Pub. No. WO 89/07110,and PCT Patent Pub. No. WO 89/07111) and GHRP-2 (described in PCT PatentPub. No. WO 93/04081), as well as hexarelin (J. Endocrinol Invest.,15(Suppl 4), 45 (1992)). Other compounds which stimulate the release ofendogenous growth hormone are disclosed, for example, in the following:U.S. Pat. No. 3,239,345; U.S. Pat. No. 4,036,979; U.S. Pat. No.4,411,890; U.S. Pat. No. 5,206,235; U.S. Pat. No. 5,283,241; U.S. Pat.No. 5,284,841; U.S. Pat. No. 5,310,737; U.S. Pat. No. 5,317,017; U.S.Pat. No. 5,374,721; U.S. Pat. No. 5,430,144; U.S. Pat. No. 5,434,261;U.S. Pat. No. 5,438,136; EPO Patent Pub. No. 0,144,230; EPO Patent Pub.No. 0,513,974; PCT Patent Pub. No. WO 94/07486; PCT Patent Pub. No. WO94/08583; PCT Patent Pub. No. WO 94/11012; PCT Patent Pub. No. WO94/13696; PCT Patent Pub. No. WO 94/19367; PCT Patent Pub. No. WO95/03289; PCT Patent Pub. No. WO 95/03290; PCT Patent Pub. No. WO95/09633; PCT Patent Pub. No. WO 95/11029; PCT Patent Pub. No. WO95/12598; PCT Patent Pub. No. WO 95/13069; PCT Patent Pub. No. WO95/14666; PCT Patent Pub. No. WO 95/16675; PCT Patent Pub. No. WO95/16692; PCT Patent Pub. No. WO 95/17422; PCT Patent Pub. No.

WO 95/17423; Science, 26 1640-1643 (Jun. 11, 1993); Ann. Rep. Med.

Chem., 28, 177-186 (1993); Bioorg. Med. Chem. Ltrs., 4(22),2709-2714(1994); and Proc. Natl. Acad. Sci. USA 92,7001-7005 (July 1995).

Representative preferred growth hormone secretagoues employed in thepresent combination include the following:

1)N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(1H-indol-3-yl)ethyl]-2-amino-2-methyl-propanamide;

2)N-[1(R)-[(1,2-Dihydro-1-methanecarbonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(1H-indol-3-yl)ethyl]-2-amino-2-methyl-propanamide;

3)N-[1(R)-[(1,2-Dihydro-1-benzenesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(1H-indol-3-yl)ethyl]-2-amino-2-methyl-propanamide;

4) N-[1(R)-[(3,4-Dihydro-spiro[2H-1-benzopyran-2,4'-piperidin]-1'-yl)carbonyl]-2-(1H-indol-3-yl)ethyl]-2-amino-2-methylpropanamide;

5)N-[1(R)-[(2-Acetyl-1,2,3,4-tetrahydrospiro[isoquinolin-4,4'-piperidinl]-1'-yl)carbonyl]-2-(indol-3-yl)ethyl]-2-amino-2-methyl-propanamide;

6)N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide;

7)N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamidemethanesulfonate;

8)N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(2',6'-difluorophenylmethyloxy)ethyl]-2-amino-2-methylpropanamide;

9)N-[1(R)-[(1,2-Dihydro-1-methanesulfonyl-5-fluorospiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide;

10)N-[1(S)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenylmethylthio)ethyl]-2-amino-2-methylpropanamide;

11)N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-3-phenylpropyl]-2-amino-2-methyl-propanamide;

12)N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-3-cyclohexylpropyl]-2-amino-2-methyl-propanamide;

13)N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-4-phenylbutyl]-2-amino-2-methyl-propanamide;

14)N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(5-fluoro-1H-indol-3-yl)ethyl]-2-amino-2-methylpropanamide;

15)N-[1(R)-[(1,2-Dihydro-1-methanesulfonyl-5-fluorospiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(5-fluoro-1H-indol-3-yl)ethyl]-2-amino-2-methylpropanamide;

16)N-[1(R)-[(1,2-Dihydro-1-(2-ethoxycarbonyl)methylsulfonylspiro-[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(1H-indol-3-yl)ethyl]-2-amino-2-methylpropanamide;

17)N-[1(R)-[(1,2-Dihydro-1,1-dioxospiro[3H-benzothiophene-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide;

and pharmaceutically acceptable salts thereof.

The compounds of the invention may also be used in combination withbisphosphonates (bisphosphonic acids) and other agents, such as growthhormone secretagogues, e.g. MK-0677, for the treatment and theprevention of disturbances of calcium, phosphate and bone metabolism, inparticular, for the prevention of bone loss during therapy with the GnRHantagonist, and in combination with estrogens, progesterones and orandrogens for the prevention or treatment of bone loss or hypogonadalsymptoms such as hot flashes during therapy with the GnRH antagonist.

Bisphosphonates (bisphosphonic acids) are known to inhibit boneresorption and are useful for the treatment of bone lithiasis asdisclosed in U.S. Pat. No. 4,621,077 to Rosini, et al.

The literature discloses a variety of bisphosphonic acids which areuseful in the treatment and prevention of diseases involving boneresorption. Representative examples may be found in the following: U.S.Pat. No. 3,251,907; U.S. Pat. No. 3,422,137; U.S. Pat. No. 3,584,125;U.S. Pat. No. 3,940,436; U.S. Pat. No. 3,944,599; U.S. Pat. No.3,962,432; U.S. Pat. No. 4,054,598; U.S. Pat. No. 4,267,108; U.S. Pat.No. 4,327,039; U.S. Pat. No. 4,407,761; U.S. Pat. No. 4,578,376; U.S.Pat. No. 4,621,077; U.S. Pat. No. 4,624,947; U.S. Pat. No. 4,746,654;U.S. Pat. No. 4,761,406; U.S. Pat. No. 4,922,007; U.S. Pat. No.4,942,157; U.S. Pat. No. 5,227,506; U.S. Pat. No. 5,270,365; EPO PatentPub. No. 0,252,504; and J. Org. Chem., 36, 3843 (1971).

The preparation of bisphosphonic acids and halo-bisphosphonic acids iswell known in the art. Representative examples may be found in the abovementioned references which disclose the compounds as being useful forthe treatment of disturbances of calcium or phosphate metabolism, inparticular, as inhibitors of bone resorption.

Preferred bisphosphonates are selected from the group of the followingcompounds: alendronic acid, etidrononic acid, clodronic acid, pamidronicacid, tiludronic acid, risedronic acid,6-amino-1-hydroxy-hexylidene-bisphosphonic acid, and1-hydroxy-3(methylpentylamino)-propylidene-bisphosphonic acid; or anypharmaceutically acceptable salt thereof. A particularly preferredbisphosphonate is alendronic acid (alendronate), or a pharmaceuticallyacceptable salt thereof. An especially preferred bisphosphonate isalendronate sodium, including alendronate sodium trihydrate. Alendronatesodium has received regulatory approval for marketing in the UnitedStates under the trademark FOSAMAX®.

Additionally, a compound of the present invention may be co-administeredwith a 5a-reductase 2 inhibitor, such as finasteride or epristeride; a5a-reductase 1 inhibitor such as 4,7b-dimethyl-4-aza-5a-cholestan-3-one,3-oxo-4-aza-4,7b-dimethyl-16b-(4-chlorophenoxy)-5a-androstane, and3-oxo-4-aza-4,7b-dimethyl-16b-(phenoxy)-5a-androstane as disclosed in WO93/23420 and WO 95/11254; dual inhibitors of 5a-reductase 1 and5a-reductase 2 such as3-oxo-4-aza-17b-(2,5-trifluoromethylphenyl-carbamoyl)-5a-androstane asdisclosed in WO 95/07927; antiandrogens such as flutamide, casodex andcyproterone acetate, and alpha-1 blockers such as prazosin, terazosin,doxazosin, tamsulosin, and alfuzosin.

Further, a compound of the present invention may be used in combinationwith growth hormone, growth hormone releasing hormone or growth hormonesecretagogues, to delay puberty in growth hormone deficient children,which will allow them to continue to gain height before fusion of theepiphyses and cessation of growth at puberty.

For combination treatment with more than one active agent, where theactive agents are in separate dosage formulations, the active agents maybe administered separately or in conjunction. In addition, theadministration of one element may be prior to, concurrent to, orsubsequent to the administration of the other agent.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example, magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy beans, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

Compounds of Formula I may also be administered in the form of asuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compound of Formula I are employed. (For purposesof this application, topical application shall include mouth. washes andgargles.)

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transdermal skin patches wellknown to those of ordinary skill in the art. To be administered in theform of a transdermal delivery system, the dosage administration will,of course, be continuous rather than intermittent throughout the dosageregimen. Compounds of the present invention may also be delivered as asuppository employing bases such as cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound thereof employed. A physician or veterinarian of ordinary skillcan readily determine and prescribe the effective amount of the drugrequired to prevent, counter, arrest or reverse the progress of thecondition. Optimal precision in achieving concentration of drug withinthe range that yields efficacy without toxicity requires a regimen basedon the kinetics of the drug's availability to target sites. Thisinvolves a consideration of the distribution, equilibrium, andelimination of a drug. Preferably, doses of the compound of structuralformula I useful in the method of the present invention range from 0.01to 1000 mg per adult human per day. Most preferably, dosages range from0.1 to 500 mg/day. For oral administration, the compositions arepreferably provided in the form of tablets containing 0.01 to 1000milligrams of the active ingredient, particularly 0.01, 0.05, 0.1, 0.5,1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of theactive ingredient for the symptomatic adjustment of the dosage to thepatient to be treated. An effective amount of the drug is ordinarilysupplied at a dosage level of from about 0.0002 mg/kg to about 50 mg/kgof body weight per day. The range is more particularly from about 0.001mg/kg to 1 mg/kg of body weight per day.

Advantageously, the active agent of the present invention may beadministered in a single daily dose, or the total daily dosage may beadministered in dividend doses of two, three or four times daily.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

The following examples illustrate the preparation of some of hecompounds of the invention and are not to be construed as limiting heinvention disclosed herein.

EXAMPLE 1 ##STR25## Step 1A2-[3-(2-Aminoethyl)-2-(3,5-dimethyl-phenyl)-1H-indol-5yl]-2-methylpropionicacid ethyl ester

A mixture of 10.50 g of ethyl 2-(4-hydrazinophenyl)-2-methylpropionate,10.55 g of 3-chloropropyl 3,5-dimethylphenyl ketone, and 200 mL ofabsolute ethanol was stirred under nitrogen and heated to reflux. After12 hours, the mixture was cooled and filtered. The solid on the filterwas washed with additional small volumes of ethanol. The filtrate wastreated with 4 mL of concentrated sulfuric acid and stirred at refluxunder nitrogen for 4 days. The cooled mixture was stirred in an ice bathas a solution of sodium ethoxide (21% w/w in ethanol) was added dropwiseuntil the mixture was basic by pH paper. The mixture was filtered andconcentrated in vacuo at 30° C. The residue was partitioned betweendiethyl ether and water, with some saturated aqueous sodium chloridesolution added to assist in separation of the layers. The aqueous phasewas washed with an additional 100 mL of ether. The combined organicextracts were dried over sodium sulfate, filtered, and concentrated invacuo. The residual gum was purified by flash chromatograpy on silicagel (elution with 97:3:0.3 and then 95:5:0.5 methylenechloride:methanol:ammonium hydroxide) to give the title compound (3.9g).

Step 1B 2-[3-(2-tert-Butoxycarbonylaminoethyl)-2-(3,5dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid ethyl ester

To a solution of2-[3-(2-aminoethyl)-2-(3,5-dimethyl-phenyl)-1H-indol-5-yl]-2-methylpropionicacid ethyl ester (763 mg in 7 mL tetrahydrofuran) at 0° C. was added asolution of 682 mg di-tert-butyl dicarbonate in 3 mL tetrahydrofuranfollowed by a solution of 432 mg poatssium carbonate in 3 mL water andthe resulting suspension stirred vigourously at 0° C. After 10 minutes,the reaction was concentrated in vacuo and the residue dissolved inethyl acetate. The organic portion was washed with brine then dried overmagnesium sulfate and concentrated in vacuo. The residue was purified byflash chromatography on silica gel (hexane:ethyl acetate, 90:10; then80:20; then 70:30) to give the title compound (910 mg).

Step 1C2-[3-(2-tert-Butoxycarbonylaminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionicacid

A suspension of2-[3-(2-tert-butoxycarbonylaminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionicacid ethyl ester (910 mg in 30 mL methanol and 9.5 mL of 2N aqueouspotassium hydroxide) was heated to 95° C. on an oil bath. After 8 hours,the mixture was cooled to room temperature and the volatile organicsremoved in vacuo. The aqueous portion was washed with ethyl acetate andthe acidified to pH 4 by the addition of 1N hydrochloric acid. This wasthen extracted with ethyl acetate and the organic portion dried overmagnesium sulfate. Concentration in vacuo gave the crude title compoundin quantitative yield.

Step 1D{2-[5-[2-(7-Azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-oxo-ethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}carbamicacid tert-butyl ester

To a suspension of2-[3-(2-tert-butoxycarbonylaminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionicacid (856 mg in 8.0 mL methylene chloride) at 0° C. was added 310 mg of1-hydroxybenzotriazole (HOBt)followed by 400 mg1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) andthe mixture stirred at low temperature for 90 minutes. At this time, asolution of 7-aza-bicyclo [2.2.1]heptane hydrochloride (632 mg in amixture of 2.0 mL methylene chloride and 0.66 mL triethylamine) wasadded and the mixture warmed to room temperature. The reaction wasquenched after 24 hours by dilution with methylene chloride and washingwith half-saturated brine. The combined organics were dried overmagnesium sulfate and the concentrate purified by flash chromatographyon silica gel (hexane:ethyl acetate, 70:30; then 60:40; then 50:50; then40:60) to give the title compound (736 mg).

Step 1E2-[3-(2-Aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-1-(7-azabicyclo[2.2.1]hept-7-yl)-2-methyl-propan-1-one

To a solution of{2-[5-[2-(7-azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-oxo-ethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}carbamic acid tert-butyl ester (728 mg in 30 mL methylene chloride) at0° C. was added 1.5 mL anisole followed by 10.5 mL trifluoroacetic acidand the mixture stirred at 0° C. After 2 hours, the mixture wasconcentrated in vacuo and the residual acid quenched by the addition of10% ammonium hydroxide in methanol. The concentrated was then purifiedby flash chromatography on silica gel (methylene chloride:10% ammoniumhydroxide in methanol, 95:5; then 92:8) to give the title compound (627mg).

Step 1F1-(7-Aza-bicyclo[2.2.1]hept-7-yl)-2-[3{2-[bis-(5-pyridin-yl-thiophen-2-ylmethyl)amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropan-1-one

To a solution of2-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-1-(7-azabicyclo[2.2.1]hept-7-yl)-2-methyl-propan-1-onein a mixture of dry chloroform and methanol at 0° C. was added magnesiumsulfate followed by 2.5 equivalents of5-pyridin-3-yl-thiophene-2-carbaldehyde and the mixture stirred at lowtemperature. After 40 minutes, acetic acid is added followed by asolution of sodium cyanoborohydride in methanol and the mixture allowedto warm to room temperature. After completion, the reaction is quenchedby the addition of saturated aqueous sodium bicarbonate, extracted withmethylene chloride and the combined organics washed sequentially withwater and brine. Purification of the concentrate by preparative tic onsilica gel gives the title compound.

PREPARATION OF SYNTHETIC INTERMEDIATES Ethyl2-(4-hydrazinophenyl)-2-methylpropionate

Step A: Ethyl (+/-)-2-(4-nitrophenyl)propionate

To a solution of 9.76 g (50 mmol) of (+/-)-2-(4-nitrophenyl) propionicacid in 150 mL of absolute ethanol was added 3.0 mL of concentratedsulfuric acid. The resulting solution was stirred at reflux undernitrogen. After 6 hours, the solution was cooled and stirred vigorouslyas 250 mL of saturated aqueous sodium bicarbonate solution was addedgradually (Caution: foaming). The mixture was then partitioned between750 mL of ethyl acetate and 500 mL of water. The organic layer waswashed with 100 mL of saturated aqueous sodium bicarbonate solution andthen with 100 mL of saturated aqueous sodium chloride solution. Theorganic phase was dried over magnesium sulfate, filtered, andconcentrated in vacuo to give 10.86 g (97%) of an oil; homogeneous byTLC in 9:1 hexane-ethyl acetate. 400 MHz ¹ H NMR (CDCl₃) was consistentwith the assigned structure.

Step B: Ethyl 2-methyl-2-(4-nitrophenyl)propionate

A suspension of 924 (23 mmol) of sodium hydride (60% in oil) in 21 mL ofdry N,N-dimethylformamide was stirred under nitrogen n an ice bath as asolution of 4.68 g (21 mmol) of ethyl (+/-)-2-(4-nitrophenyl)propionatein 20.5 mL of dry N,N-dimethylformamide was added gradually over about10 minutes. An intense violet color developed during the addition. Themixture was then allowed to warm to room temperature. After about 1hour, the mixture was again cooled in an ice bath as a solution of 1.44mL (3.28 g; 23 mmol) of methyl iodide in 5 mL of dryN,N-dimethylformamide was added dropwise by syringe over about 10minutes, while maintaining the internal temperature at 10-15° C. Themixture was allowed to warm to room temperature, and the color changedto brown. After 1 hour, an additional 187 mL (426 mg, 3 mmol) ofiodomethane was added. By the next day, the mixture consisted of asuspension of some grayish solid in a golden liquid. It was stirredvigorously and quenched by gradual addition of 10 mL of 5% aqueouspotassium bisulfate solution. The mixture was partitioned between 400 mLof diethyl ether and 400 mL of water. The organic layer was washed withan additonal 3×400 mL of water and then with 50 mL of saturated aqueoussodium chloride solution. The organic phase was then dried overmagnesium sulfate, filtered, and concentrated in vacuo. Flashchromatography of the residue on silica gel (elution with 19:1hexane-ethyl acetete) yielded 4.31 g (87%) of an oil; homogeneous by TLCin 9:1 hexane-ethyl acetete. 400 MHz ¹ H NMR (CDCl₃) was consistent withthe assigned structure.

Step C: Ethyl 2-(4-Aminophenyl)-2-methylpropionate

A mixture of 4.27 g (18 mmol) of ethyl2-methyl-2-(4-nitrophenyl)propionate, 200 mg of 10% palladium on carbon,and 120 mL of absolute ethanol was shaken with hydrogen (initialhydrogen pressure 47 psig) in a pressure vessel for 2 hours. Thecatalyst was removed by filtration through Celite under nitrogen, andthe filter cake was washed with additional ethanol. Concentration of thefiltrate in vacuo at up to 50° C. gave 3.74 g (100%) of an oil;homogeneous by TLC in 4:1 hexane-EtOAc. 400 MHz ¹ H NMR (CDCl₃) wasconsistent with the assigned structure. Mass spectrum (ESI): m/e=208(M+H).

Step D: Ethyl 2-(4-hydrazinophenyl)-2-methylpropionate

A solution of 3.725 g (18 mmol) of ethyl2-(4-aminophenyl)-2-methylpropionate in 18 mL of concentratedhydrochloric acid was stirred at -10 to -5° C. in an ice-acetone bath asa solution of 1.29 g (18.7 mmol) of sodium nitrite in 7.5 mL of waterwas added dropwise over about 15 minutes. Stirring was continued at thistemperature for an additional 30 minutes. Next, a small amount ofinsoluble solid was removed by filtration into a cold receiving flask.The filtrate was then added dropwise over 10-15 minutes to a solution of20.3 g (90 mmol) of stannous chloride dihydrate in 14.5 mL ofconcentrated hydrochloric acid stirred under nitrogen in an ice-acetonebath. The addition was carried out at such a rate that the internaltemperature remained at about -5° C. A gummy material separated duringthe addition. After completion of the addition, stirring was continuedat -10 to -5° C. for 1 hour. The aqueous phase was decanted, and theresidual gum was dissolved in 250 mL of ethyl acetate. The ethyl acetatesolution was treated cautiously with 250 mL of saturated aqueous sodiumbicarbonate solution and shaken in a separatory funnel. The ethylacetate layer was washed with 50 mL of saturated aqueous sodium chloridesolution. The entire mixture was filtered before separation of thephases. The ethyl acetate phase was dried over magnesium sulfate,filtered, and concentrated in vacuo at room temperature to yield 2.59 g(65%) of an oil. 500 MHz ¹ H NMR (CDCl₃) was consistent with theassigned structure and indicated that only minor impurities werepresent.

3-Chloropropyl 3,5-dimethylphenyl ketone

Step AA: 4-Chloro-N-methoxy-N-methylbutyramide

To a solution of 4-chlorobutyryl chloride (10.0 g in 200 mL of drymethylene chloride) was added 10.4 g of N,O-dimethylhydroxylaminiehydrochloride. The mixture was stirred under nitrogen and maintainedbelow 25° C. by cooling in an ice bath as necessary while triethylamine(29.1 mL)was added dropwise over about 20 minutes, resulting inprecipitation. After 1.5 hours at room temperature, the mixture wasconcentrated in vacuo. The residue was partitioned between 100 m-L ofdiethyl ether and 100 mL of saturated aqueous sodium bicarbonatesolution. The organic layer was washed with an additional 100 m-L ofsaturated sodium bicarbonate, and the aqueous fractions wereback-extracted with ether. The combined organic phases were dried oversodium sulfate, filtered, and concentrated in vacuo to give 10.5 g (90%)of an oil, which had satisfactory purity by ¹ H NMR (CDCl₃). Massspectrum (PB-NH₃ /CI): m/e=166 (M+H).

Step BB: 3-Chloropropyl 3,5-dimethylphenyl ketone

A solution of 10.2 mL (13.9 g; 72 mmol) 5-bromo-m-xylene in 200 mL ofanhydrous tetrahydrofuran was stirred under nitrogen at -78° C. as 35.8mL (84 mmol) of 2.5 M n-butyllithium in tetrahydrofuran was addeddropwise. After 15 minutes at -78° C., a solution of 10.0 g (60 mmol) of4-chloro-N-methoxy-N-methylbutyramide in 30 mL of anhydroustetrahydrofuran was added dropwise over 25-30 minutes. The resultingsolution was maintained at -78° C. for 45 minutes and then warmedbriefly to room temperature. The reaction was quenched by addition of 40mL of 2 N hydrochloric acid and then partitioned between ethyl acetateand water. The organic phase was washed with saturated aqueous sodiumbicarbonate solution and then saturated aqueous sodium chloridesolution. The organic solution was dried over sodium sulfate, filtered,and concentrated in vacuo. Flash chromatography of the residue afforded8.91 g (70%) of an oil, which had satisfactory purity by ¹ H NMR(CDCl₃).

5-Pyridin-3-yl-thiophene-2-carbaldehyde

Step AAA: Pyridine-3-boronic acid

To a solution of n-butyllithium (16 mL of a 2.5M solution in hexane=50mL dry diethyl ether) at -78° C. was added a solution of 3-bromopyridine(6 g in 15 mL diethyl ether) and the mixture stirred for 25 minutes. Atthis time trimethyl borate (4.3 mL) was added and the mixture allowed towarm to room temperature. After 1 hour the reaction was quenched by theaddition of 10 mL glacial acetic acid and 60 mL water and the mixturestirred for 18 hours at room temperature. The pH of the mixture wasadjusted to pH12 by the addition of 2M sodium hydroxide and extractedwith diethyl ether. The aqueous layer was acidified to pH 6 by thedropwise addition of 1N hydrochloric acid and extracted with methylenechloride. The combined organics were dried over magnesium sulfate andconcentrated in vacuo. The residue was triturated with 20 mLacetonitrile:water (1:1) and filtered to give the title compound (1.0g).

Step BBB: (5-pyridin-3-yl-thiophen-2-yl)-methanol

To a mixture of 153 mg (5-bromo-thiophen-2-yl)-methanol, 128 mgpyridine-3-boronic acid, and 64 mg tetrakis(triphenylphosphine)palladium was added solvent (7.3 mL toluene and 3.1 mL methanol)followed by 1.4 mL of 2.5M sodium carbonate and the mixture heated to80° C. on an oil bath. After 16 hours the mixture was cooled to roomtemperature and cocncentrated in vacuo. The residue was solvated inethyl acetate was washed sequentially with 0.5N sodium hydroxide andbrine, dried over magnesium sulfate and concentrated in vacuo.Purification by flash chromatography on silica gel (hexane:ethylacetate, 60:40; then 55:45) gave the title compound (147 mg).

Step CCC: 5-Pyridin-3-yl-thiophene-2-carbaldehyde

To a solution of (5-pyridin-3-yl-thiophen-2-yl)-methanol (144 mg in 7.5mL dry methylene chloride) was added 327 mg of the1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one and the mixturestirred at room temperature. After 4 hours, the reaction was quenched byaddition of a mixture of saturated sodium bicarbonate and saturatedsodium thiosulfite (1:1) and extracted with diethyl ether. The aqueousportion was extracted further with methylene chloride and the combinedorganics then washed with water and brine and dried over magnesiumsulfate. Purification of the concentrate by flash chromatography onsilica gel (ethyl acetate:hexane, 75:25; then 80:20) gave the titlecompound (80 mg).

EXAMPLE 2 ##STR26## Step 2A N,N-Diisopropyl-4-nitrobenzamide

A solution of 3.51 mL (2.53 g, 25 mmol) of diisopropylamine and 3.62 mL(2.63 g, 26 mmol) of triethylamine in 50 mL of anhydrous tetrahydrofuranwas stirred under nitrogen and maintained at -5° C. as a solution of4.11 g (22.1 mmol) in 10 mL of anhydrous tetrahydrofuran was addeddropwise over 15 minutes. The mixture was allowed to warm gradually toroom temperature. After 2 hours, the mixture was filtered, and thefiltrate was partitioned between diethyl ether and 1 N hydrochloricacid. The organic phase was then washed with saturated sodium carbonate₃solution, then dried over sodium sulfate and filtered. The filtrate wasconcentrated in vacuo, and the residue was flash-chromatographed onsilica gel (gradient elution with 2-5% MeOH in CH₂ C₁₂) to yield 4.77 g(86%) of yellowish crystals, mp 141.5-142° C.; homogeneous by TLC 2:1hexane-EtOAc. 500 MHz ¹ H NMR (CDCl₃) was consistent with the assignedstructure.

Step 2B 4-Amino-N,N-diisopropylbenzamide

A mixture of 4.70 g (18.8 mmol) of N,N-diisopropyl-4-nitrobenzamide, 200mg of 10% palladium on carbon, and 200 mL of 2-methoxyethanol was shakenwith hydrogen at approx. 50 psig for 6.5 hours. The catalyst was removedby filtration through diatomaceous earth under nitrogen. Concentrationof the filtrate in vacuo afforded a quantitative yield of a yellowsolid, mp 169.5-170° C.; homogeneous by TLC in 95:5 CH₂ C₁₂ -MeOH. 500MHz ¹ H NMR (CDCl₃) was consistent with the assigned structure. Massspectrum (PB-NH₃ /CI): m/e=221 (M +H).

Step 2C 4-Hydrazino-N,N-diisopropylbenzamide

Treatment of 4.2 g (19 mmol) of 4-amino-N,N-diisopropylbenzamide with 15mL of concentrated hydrochloric acid and 10 mL of water was followed byagitation. The resulting solution was maintained at approx. -3° C. as asolution of 1.32 g (19.1 mmol) of sodium nitrite in 9 mL of water wasadded dropwise. After being stirred for an additional 30 minutes at thistemperature, this solution was added portionwise to a vigorously stirredsolution of 15.1 g (66.7 mmol) of stannous chloride dihydrate in 15 mLof concentrated hydrochloric acid, which was maintained at about -10° C.After completion of the addition, the mixture was stirred at thistemperature for 5 minutes and then allowed to warm to room temperature.At this point, it was again cooled and basified by gradual addition of25 mL of 50% sodium hydroxide. The resulting precipitate was collectedon a filter and partitioned between tetrahydrofuran and 5 N sodiumhydroxide in a 2:1 ratio. The aqueous layer was extracted 3 times withtetrahydrofuran. The combined organic fractions were concentrated invacuo. The residue was taken up in CH₂ Cl₂ -EtOAc, dried over sodiumsulfate, filtered, and reconcentrated to give 3.55 g (80%) of semisolid;homogeneous by TLC in 95:5 CH₂ Cl₂ -MeOH. 500 MHz 1H NMR (CDCl₃) wasconsistent with the assigned structure. Mass spectrum (PB-NH₃ /CI):m/e=236 (M+H).

Step 2D 3-(2-Aminoethyl)-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylicacid diisopropylamide

A solution of 3.51 g (14.9 mmol) 4-hydrazino-N,N-diisopropylbenzamide(from Step 3) in 18 mL of 2-methoxyethanol was stirred at 100° C. undernitrogen as 3.77 g (17.8 mmol) of 3-chloropropyl 3,5-dimethylphenylketone in 7 mL of 2-methoxyethanol was added dropwise over 20 minutes.The solution was stirred at this temperature for 5 hours, then cooledand filtered to remove a solid (a tetrahydro-pyridazine by-product). Thefiltrate was concentrated in vacuo, and the residue was purified byflash chromatography on silica gel (elution with 95:5 CH₂ C₁₂ -MeOHfollowed by a gradient of 98:2:0.2 to 92:8:0.8 CH₂ C₂ Cl₂ -MeOH-concd.NH₄ OH) gave 1.78 g (31%) of a brownish, stiff foam; satisfactory purityby TLC in 95:5:0.5 CH₂ C₂ -MeOH-concd. NH₄ OH. 500 MHz ¹ H NMR (CDCl₃)was consistent with the assigned structure. Mass spectrum (PB-NH₃ /CI):m/e=392.2 (M+H).

Step 2E3-{2-[Bis-(5-pyridin-3-yl-thiophen-2-ylmethyl)amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylicacid diisopropylamide

To a solution of3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic aciddiisopropylamide in a mixture of dry chloroform and methanol at 0° C. isadded magnesium sulfate followed by 2.5 equivalents of5-pyridin-3-yl-thiophene-2-carbaldehyde and the mixture stirred at lowtemperature. After 40 minutes, acetic acid is added followed by asolution of sodium cyanoborohydride and the mixture allowed to warm toroom temperature. After completion, the reaction is quenched by theaddition of saturated aqueous sodium bicarbonate, extracted withmethylene chloride and the combined organics washed sequentially withwater and brine. Purification of the concentrate by preparative tlc onsilica gel gives the title compound.

What is claimed is:
 1. A compound of the formula ##STR27## wherein A isR₂₂ -[thiophene]-R₂₂ -;B is optionally absent, --OR₂₂ --, --C(═O)R₂₂ --,--S(O)_(n) R₂₂ --, --NR₁₈ R₂₂ --, --OC(═O)R₂₂ --, --C(═O)OR₂₂,--OS(O)_(n) R₂₂ -- or --S(O)_(n) OR₂₂ --; R₀ is hydrogen, C₁ -C₆ alkyl,substituted C₁ -C₆ alkyl, wherein the substituents are as defined below;aryl, substituted aryl, aralkyl or substituted aralkyl, wherein thesubstituents are as defined for R₃, R₄ and R₅ ; R₁ is ##STR28## thenitrogen atoms contained in the R₁ heteroaromatic rings may exist eitheras drawn or, when chemically allowed, in their oxidized (N→O) state; R₂is A--B--R₁ ; R₃, R₄ and R₅ are independently hydrogen, C₁ -C₆ alkyl,substituted C₁ -C₆ alkyl, C₂ -C₆ alkenyl, substituted C₂ -C₆ alkenyl,CN, nitro, C₁ -C₃ perfluoroalkyl, C₁ -C₃ perfluoroalkoxy, aryl,substituted aryl, aralkyl, substituted aralkyl, R₁₁ O(CH₂)_(p)--,--(CH₂)_(p) S(O)_(n) R₁₇ or halogen; wherein R₁₇ is hydrogen, C₁ -C₆alkyl, C₁ -C₃ perfluoroalkyl, aryl or substituted aryl; or R₃ and R₄taken together form a carbocyclic ring of 3-7 carbon atoms; R₆ ishydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, aryl, substitutedaryl, C₁ -C₃ perfluoroalkyl, CN, NO₂, halogen, R₁₆ O(CH₂)_(p) --; R₇ ishydrogen, C₁ -C₆ alkyl, or substituted C₁ -C₆ alkyl; R₈ is hydrogen,C(O)OR₉, C(O)NR₁₁ R₁₂, NR₁₁ R₁₂, C(O)R₁₁, NR₁₂ C(O)R₁₁, NR₁₂ C(O)NR₁₁R₁₂, NR₁₂ S(O)₂ R₁₁, NR₁₂ S(O)₂ NR₁₁ R₁₂, OC(O)R₁₁, OC(O)NR₁₁ R₁₂, OR₁₁,SO_(n) R₁₁, S(O)_(n) NR₁₁ R₁₂, R₉ and R_(9a) are independently hydrogen,C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl; aryl or substituted aryl,aralkyl or substituted aralkyl when m≠0; or R₉ and R_(9a) taken togetherform a carbocyclic ring of 3-7 atoms or ##STR29## when m≠0; R₁₀ andR_(10a) are independently hydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl; or R₁₀and R_(10a) taken together form a carbocyclic ring of 3-7 atoms or##STR30## R₉ and R₁₀ when taken together form a carbocyclic ring of 3-7carbon atoms when m≠0; or R₁₁ and R₁₂ are independently hydrogen, C₁ -C₆alkyl, substituted C₁ -C₆ alkyl, aryl, substituted aryl, aralkyl,substituted aralkyl, a carbocyclic ring of 3-7 atoms, a substitutedcarbocyclic ring containing 3-7 atoms, R11 and R12 taken together form abridged aza bicyclic ring of six to seven carbon atoms; R₁₃ is hydrogen,OH, NR₇ R₈, NR₁₆ SO₂ (C₁ -C₆ alkyl), NR₁₆ SO₂ (substituted C₁ -C₆alkyl), NR₁₆ SO₂ (aryl), NR₁₆ SO₂ (substituted aryl), NR₁₆ SO₂ (C₁ -C₃perfluoroalkyl); SO₂ NR₁₆ (C₁ -C₆ alkyl), SO₂ NR₁ i(substituted C₁ -C₆alkyl), SO₂ NR₁₁ (aryl), SO₂ NR₁₆ (substituted aryl), SO₂ NR₁₆ (C₁ -C₃perfluoroalkyl); SO₂ NR₁₆ (C(O)C₁ -C₆ alkyl); SO₂ NR₁₆ (C(O)--substituted C₁ -C₆ alkyl); SO₂ NR₁₆ (C(O)-aryl); SO₂ NR₁₆ (C(O)--substituted aryl); S(O)_(n) (C₁ -C₆ alkyl); S(O)_(n) (substituted C₁ -C₆alkyl), S(O)_(n) (aryl), S(O)_(n) (substituted aryl), C₁ -C₃perfluoroalkyl, C₁ -C₃ perfluoroalkoxy, C₁ -C₆ alkoxy, substituted C₁-C₆ alkoxy, COOH, halogen, NO₂ or CN; R₁₄ and R₁₅ are independentlyhydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, C₂ -C₆ alkenyl,substituted C₂ -C₆ alkenyl, CN, nitro, C₁ -C₃ perfluoroalkyl, C₁ -C₃perfluoroalkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl,R₁₆ O(CH₂)_(p) --, R₁₆ C(O)O(CH₂)_(p) --, R₁₆ OC(O) (CH₂)_(p) --,--(CH₂)_(p) S(O)_(n) R₁₇, --(CH₂)_(p) C(O) N(R₁₆)₂ or halogen; whereinR₁₇ is hydrogen, C₁ -C₆ alkyl, C₁ -C₃ perfluoroalkyl, aryl orsubstituted aryl; R₁₆ is hydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, acarbocyclic ring of 3-7 atoms or a substituted carbocyclic ringcontaining 3-7 atoms; R₁₈ is hydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆alkyl, C(O)OR₁₆, C(O)N(R₁₆)₂, C(O)R₁₆, S(O)_(n) R₁₆ ; R₂₂ is C₀ -C₄alkyl, substituted C₁ -C₄ alkyl; X is N, O, S(O)_(n), C(O)_(n), (CR₁₁R₁₂)_(p), a single bond to R₈ ; when X is O, S(O)n, C(O), or CR₁₁ R₁₂only R₈ is possible; m is 0,1, 2 or 3; n is 0, 1 or 2; p is 0, 1, 2, 3or 4; and the alkyl, cycloalkyl, alkenyl and alkynyl substituents areselected from C₁ -C₆ alkyl, C₃ -C₇ cycloalkyl, aryl, substituted aryl,aralkyl, substituted aralkyl, hydroxy, oxo, cyano, C₁ -C₆ alkoxy,fluoro, C(O)OR₁₁, aryl C₁ -C₃ alkoxy, substituted aryl C₁ -C₃ alkoxy,and the aryl substituents are as defined for R₃, R₄ and R₅ ;or apharmaceutically acceptable addition salt and/or hydrate thereof, orwhere applicable, a geometric or optical isomer or racemic mixturethereof.
 2. The compound according to claim 1 of the formula ##STR31##wherein: A is R₂₂ -[thiophene]-R₂₂ -;R₀ is hydrogen; R₁ is ##STR32## thenitrogen atoms contained in the R₁ heteroaromatic rings may exist eitheras drawn or, when chemically allowed, in their oxidized (N→O) state; R₃,R₄ and R₅ are independently hydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆alkyl or halogen; R₈ is C(O)NR₁₁ R₁₂, or R₁₁ and R₁₂ are independentlyhydrogen, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, aryl, substitutedaryl, aralkyl, substituted aralkyl, a carbocyclic ring of 3-7 atoms, asubstituted carbocyclic ring containing 3-7 atoms, R11 and R12 takentogether form a bridged aza bicyclic ring of six to seven carbon atoms;X is (CR₁₁ R₁₂)_(p) ;or a pharmaceutically acceptable addition saltand/or hydrate thereof, or where applicable, a geometric or opticalisomer or racemic mixture thereof.
 3. The compound according to claim 1of the formula ##STR33## or a pharmaceutically acceptable addition saltand/or hydrate thereof, or where applicable, a geometric or opticalisomer or racemic mixture thereof.
 4. The compound according to claim 1of the formula ##STR34## or a pharmaceutically acceptable addition saltand/or hydrate thereof, or where applicable, a geometric or opticalisomer or racemic mixture thereof.
 5. A pharmaceutical composition whichcomprises an effective amount of a compound as defined in claim 1 and apharmaceutically acceptable carrier therefor.
 6. A pharmaceuticalcomposition made by combining the compound of claim 1 and apharmaceutically acceptable carrier therefor.
 7. A process for making apharmaceutical composition comprising combining a compound of claim 1and a pharmaceutically acceptable carrier.